The central objective of this proposal is to demonstrate the benefits of optical spectroscopy for the screening, management, and prevention of colorectal cancer (CRC) as compared to current standard practices. Two complementary applications will be tested using the same platform: Using elastic-scattering spectroscopy (ESS) to distinguish reliably between neoplastic and non-neoplastic polyps, and using ESS, low- coherence enhanced backscattering spectroscopy (LEBS), and partial wave spectroscopy (PWS) for sensing the field effect of carcinogenesis (FEC). The specific objectives are: 1. To conduct a prospective clinical study using ESS for real-time histological assessment of polyps. We will prospectively test and validate algorithms that we have designed for ESS classification of polyps, using the ASGE-PIVI guidelines as performance benchmarks. 2. Clinical studies of field effect, and combined applications study. We will concurrently collect algorithm-training and validation data for sensing of FEC with ESS, during routine colonoscopy procedures. With the same patients and at the same procedure, we will look at ESS as a CRC risk assessment tool and its relationship, if any, with improvements in efficiency and success rate of finding neoplastic polyps for polypectomy. In addition, we will use optical measurements obtained with LEBS and rectal brushings analyzed with PWS to cross-validate FEC sensing results obtained with ESS. 3. Instrumentation: Implement system enhancements and tool design for clinical friendliness. We will establish standardization and calibration procedures to make instruments robust to variations in clinical environment, and develop next-generation clinical hardware and software interfaces. This will ensure that comparable results are obtained among different operators and sites. Integration of ESS and LEBS into a single hybrid system box will be enabled as required. Endoscope-mediated tools for guiding polypectomy and FEC-sensing will be designed to be low-cost and disposable. Methodology: Candidate subjects for this study will be drawn from an extant pool of patients who are scheduled for routine or surveillance colonoscopy by their physician or as the result of a prior clinical evaluation or a pre-existing condition. Upon obtaining a signed Informed Consent, all patients will receive standard treatment. The main deviation from the normal examination and biopsy procedure will be to take an optical measurement prior to each biopsy and of surrounding colonic mucosa, and a rectal sample for brush cytology during the colonoscopy. When biopsy is required, prior to the standard physical biopsy, an optical biopsy will be taken of the exact same tissue with the ESS optical forceps. The biopsy will be sent for histopathology, as per standard of care, and reviewed by three independent pathologists blinded to the spectroscopic results. Measurements of normal colonic mucosa will also be taken along several segments of the colon with ESS. Additionally, optical measurements of rectal mucosa will be obtained with LEBS, as well as rectal brushings that will be analyzed with PWS. ESS spectra from polyps will be correlated to the majority diagnosis from the pathologists. ESS, LEBS, and PWS measurements from normal colonic tissue will be assigned as to belonging to a neoplastic or non-neoplastic field based on findings during the procedure. Diagnostic algorithms will be trained and tested using these correlated optical data. Data for identification of FEC biomarkers will be collected from several sources to rule out possible confounders.